Large granular lymphocyte (LGL) leukemia results from chronic proliferation of either CD3- or CD3+ LGL. The two different subsets of leukemic LGL offer an opportunity to examine the activation of the two classes of non- MHC-restricted cytotoxic lymphocytes, ie, CD3- LGL (natural killer cells) and CD3+ LGL (non-MHC-restricted cytotoxic T lymphocytes). The mechanism of activation leading to proliferation (Specific Aim #1) and cytotoxicity (Specific Aim #2) will be examined. Activation of leukemic LGL will be produced using anti-CD3 monoclonal antibody or lymphokines such as IL-2, IL-4, or IL-6. Lymphokine secretion, expression of lymphokine cell surface receptors, and expression of lymphokine gene transcripts will be measured before and after activation. These studies will allow evaluation of 1) whether aberrant or autocrine secretion of lymphokines such as IL-6 is associated with pathogenesis of LGL, 2) whether the mechanism of activation differs for CD3- and CD3+ LGL, 3) whether the mechanism of proliferative activation differs from that producing activation of cytotoxicity, and 4) whether anti-CD3 monoclonal antibody, IL-2, IL-4, and IL-6 provide different triggering signals for activation.